TY - JOUR T1 - Molecular and pharmacological characterization of insulin icodec: a new basal insulin analog designed for once-weekly dosing JF - BMJ Open Diabetes Research & Care JO - BMJ Open Diab Res Care DO - 10.1136/bmjdrc-2021-002301 VL - 9 IS - 1 SP - e002301 AU - Erica Nishimura AU - Lone Pridal AU - Tine Glendorf AU - Bo Falk Hansen AU - František Hubálek AU - Thomas Kjeldsen AU - Niels Rode Kristensen AU - Anne Lützen AU - Karsten Lyby AU - Peter Madsen AU - Thomas Åskov Pedersen AU - Rasmus Ribel-Madsen AU - Carsten Enggaard Stidsen AU - Hanne Haahr Y1 - 2021/08/01 UR - http://drc.bmj.com/content/9/1/e002301.abstract N2 - Introduction Insulin icodec is a novel, long-acting insulin analog designed to cover basal insulin requirements with once-weekly subcutaneous administration. Here we describe the molecular engineering and the biological and pharmacological properties of insulin icodec.Research design and methods A number of in vitro assays measuring receptor binding, intracellular signaling as well as cellular metabolic and mitogenic responses were used to characterize the biological properties of insulin icodec. To evaluate the pharmacological properties of insulin icodec in individuals with type 2 diabetes, a randomized, double-blind, double-dummy, active-controlled, multiple-dose, dose escalation trial was conducted.Results The long half-life of insulin icodec was achieved by introducing modifications to the insulin molecule aiming to obtain a safe, albumin-bound circulating depot of insulin icodec, providing protracted insulin action and clearance. Addition of a C20 fatty diacid-containing side chain imparts strong, reversible albumin binding, while three amino acid substitutions (A14E, B16H and B25H) provide molecular stability and contribute to attenuating insulin receptor (IR) binding and clearance, further prolonging the half-life. In vitro cell-based studies showed that insulin icodec activates the same dose-dependent IR-mediated signaling and metabolic responses as native human insulin (HI). The affinity of insulin icodec for the insulin-like growth factor-1 receptor was proportionately lower than its binding to the IR, and the in vitro mitogenic effect of insulin icodec in various human cells was low relative to HI. The clinical pharmacology trial in people with type 2 diabetes showed that insulin icodec was well tolerated and has pharmacokinetic/pharmacodynamic properties that are suited for once-weekly dosing, with a mean half-life of 196 hours and close to even distribution of glucose-lowering effect over the entire dosing interval of 1 week.Conclusions The molecular modifications introduced into insulin icodec provide a novel basal insulin with biological and pharmacokinetic/pharmacodynamic properties suitable for once-weekly dosing.Trial registration number NCT02964104.For the non-clinical studies, data associated with this work are present in the paper. Data and reagents may be made available, on reasonable request, from Novo Nordisk A/S under a materials transfer agreement. For the clinical trial, individual participant data will be shared in data sets in a deidentified/anonymized format. Datasets from Novo Nordisk sponsored clinical research completed after 2001 for product indications approved in both the EU and USA will be shared. Trial protocol and redacted Clinical Trial Report will be available according to Novo Nordisk data sharing commitments. The data will be available permanently after research completion and approval of product and product use in both EU and USA. Data will be shared with bona fide researchers submitting a research proposal requesting access to data. Data will be shared for analyses as approved by the Independent Review Board (IRB) according to the IRB Charter (see novonordisk-trials.com). Data will be available through an access request proposal form, and the access criteria can be found at novonordisk-trials.com. The data will be made available on a specialized SAS data platform. ER -